CN103328495A - Chlorination of carbohydrates and carbohydrate derivatives - Google Patents
Chlorination of carbohydrates and carbohydrate derivatives Download PDFInfo
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- CN103328495A CN103328495A CN2012800061432A CN201280006143A CN103328495A CN 103328495 A CN103328495 A CN 103328495A CN 2012800061432 A CN2012800061432 A CN 2012800061432A CN 201280006143 A CN201280006143 A CN 201280006143A CN 103328495 A CN103328495 A CN 103328495A
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- carbohydrate
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- ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
Abstract
Disclosed is a method for chlorinating a carbohydrate or a derivative thereof to produce a polychlorinated carbohydrate or a derivative thereof, such as sucralose, the method involves (i) reacting the carbohydrate or derivative thereof with a chlorinating agent to obtain a reaction mixture comprising said polychlorinated carbohydrate or derivative thereof and at least one under-chlorinated carbohydrate or derivative thereof, (ii) returning the at least one under-chlorinated carbohydrate or derivative thereof to a chlorinating step and further chlorinating the at least one under-chlorinated carbohydrate or derivative thereof to obtain the desired polychlorinated carbohydrate or derivative thereof; and (iii) optionally repeating steps (i) and (ii) "n" times where n>= 1. The polychlorinated carbohydrate or a derivative thereof is obtained in high yields.
Description
The cross reference of related application
The application requires in the U.S. Provisional Patent Application No.61/547 of submission on October 14th, 2011,356 rights and interests, and its disclosure is incorporated this paper by reference into.
Background technology
The chlorination of carbohydrate (carbohydrate) and derivative thereof (such as sugar (sugar) and ester thereof) is generally understood.For example, at United States Patent (USP) 4,980,463, disclose among WO2008/052076A2, U.S.2007/0100139A1 and the U.S.2007/0207246A1 and make the sucrose chlorination to produce Sucralose (or 4,1 ', 6 '-three chloro-4,1 ', 6 '-three deoxidation sucralose), it is the artificial sweetner of the manyfold of sucrose for sugariness.Sucralose can prepare by the chlorination of sucrose ester (such as cane sugar-6-acetic ester or Sucrose-6-benzoate).But the productive rate of the sucralose-6-ester of reporting in this area is usually lower.For example, patent ' 463 disclose the example that molar yield is 31.9% to 60% preparation Sucralose-6-benzoic ether.WO ' 076 discloses the example that molar yield is 62.5% preparation sucralose-6-acetic ester.
Aforementioned content shows, has the still unsatisfied needs that prepare many chloros carbohydrate or derivatives thereof (particularly Sucralose-6 ester) with high molar yield.
Summary of the invention
Thereby the invention provides be used to making carbohydrate or derivatives thereof chlorination high productivity produce the method for many chloros carbohydrate or derivatives thereof.The method comprises that the carbohydrate or derivatives thereof that makes at least a portion chloro deficiency reclaims and is back to chlorinating step, thereby makes the further chlorination of carbohydrate or derivatives thereof of described chloro deficiency become many chloros carbohydrate or derivatives thereof of expectation.These recovery and return step and can repeat any desired number of times, thus many chloros carbohydrate or derivatives thereof, particularly sucralose-6-ester of high yield obtained.
Therefore, the invention provides following one or more advantage: the productive rate that has improved many chloros carbohydrate ester of expectation, waste streams (waste stream) and/or the processing of the carbohydrate ester of part chloro or chloro deficiency have been reduced, potentially reduced energy demand, reduce Raw Material Demand, and/or improved the economy of technique.Therefore, the present invention also provides the economical advantage at process aspect known in the art.
Detailed Description Of The Invention
Therefore, the invention provides be used to making the chlorination of carbohydrate or derivatives thereof to produce the method for many chloros carbohydrate or derivatives thereof, described many chloros carbohydrate or derivatives thereof has the chlorine atom of desired number at the desired location of its molecular structure, described method comprises:
(i) make carbohydrate or derivatives thereof and chlorination reaction, obtain comprising the reaction mixture of the carbohydrate or derivatives thereof of described many chloros carbohydrate or derivatives thereof and at least a chloro deficiency;
(ii) make the carbohydrate or derivatives thereof of described at least a chloro deficiency be back to chlorinating step and the further carbohydrate or derivatives thereof of the described at least a chloro deficiency of chlorination, obtain many chloros carbohydrate or derivatives thereof of expecting; With
(iii) randomly repeating step (i) and (ii) " n " inferior, n 〉=1 wherein.
According to the present invention, have at least two, three, four, five or any suitable carbohydrate or derivatives thereof of more hydroxyls all can carry out chlorination.In one embodiment, the carbohydrate or derivatives thereof has at least 3 hydroxyls by the present invention's method chlorination.
Carbohydrate can be monose, oligosaccharides or polysaccharide.Oligosaccharides can be disaccharides, trisaccharide, tetrose or high-grade sugar (higher saccharide) more.An example of disaccharides is sucrose.More the example of high-grade sugar comprises starch, Mierocrystalline cellulose, hemicellulose, natural gum, dextran (dextran), gellan (gellan), amylopectin, Sclerotium gum, the blue glue (welan) of dimension, xanthan gum, agar, phycocolloid (algin), carrageenin (carrageenan), furcellaran (furcellaran), pectin, chitin and chitosan.
In one embodiment, carbohydrate derivates can also be nucleosides (for example, uridine, deoxyuridine, adenosine, Desoxyadenosine, guanosine, pancreatic desoxyribonuclease, thymidine, deoxythymidine, cytidine, Deoxyribose cytidine) or Nucleotide (for example DNA or RNA).According to the present invention, carbohydrate derivates can be covalently bound a kind of of carbohydrate molecule and another molecule (such as any other polymer molecule) wherein.
According to one embodiment of the invention, the carbohydrate or derivatives thereof is sugared or derivatives thereof.The example of suitable sugar comprises sucrose, maltose, lactose, erythrose, threose, ribose, pectinose, wood sugar, lyxose, allose, altrose, glucose sugar, seminose, gulose, idose, semi-lactosi and talose, in particular sucrose.
In one embodiment, carbohydrate or sugar derivatives are esters.In a particular, sugar derivatives is sugar ester, more particularly sucrose ester.
According to the inventive method, many chloros carbohydrate or derivatives thereof can keep the three-dimensional chemical configuration of one or more group on the carbohydrate ring structure, and perhaps the three-dimensional chemical configuration of one or more group on the carbohydrate ring structure of many chloros carbohydrate or derivatives thereof can be different from initial carbohydrate or derivatives thereof.
An embodiment according to the inventive method, the ester of many chloros carbohydrate ester or chloro deficiency has formula: M-OC (=O) R ', wherein R ' comprises hydrophobic grouping or hydrophobic polymer, and M is that the ester that replenishes many chloros carbohydrate ester or chloro deficiency makes it complete part.For example, R ' comprises hydrophobic grouping or hydrophobic polymer, thereby octanol-water partition coefficient (Kow) LogP of the ester of many chloros carbohydrate ester or chloro deficiency or calculating (cLogP) are-0.5 or larger.LogP or cLogP value have been described the compound tendency that the oneself distributes between hot alcohol and water: to the measurement of its close ester and/or hydrophobicity.When compound unknown, but perhaps known its LogP value of physically not measuring can be used the method for calculating cLogP value so.
Several specialized procedures that can carry out above-mentioned calculating are that appearance is facile: for example, and SciFinder
TMA kind of Advanced Chemistry Development (ACD/Labs) Software V11.02 is provided.The freeware resource is also arranged, for example ChemAxon
TMProvide.
In one embodiment of the invention, the octanol-water partition coefficient LogP of the carbohydrate ester of many chloros carbohydrate ester or chloro deficiency or cLogP are 0 or greater than 0, for example 0.05 to approximately 5, and be approximately 0.5 to approximately 3 in one embodiment.For example, the cLogP of a chlorine Sucrose-6-benzoate is 0.7; The cLogP of dichlorogalactosucroand-6-benzoic ether is 1.5 (interpolate value (interpolated value)); 4,1 ', 6 '-three chloro-4 of sucralose, the cLogP of 1 ', 6 '-three deoxidations-6-O-benzoic ether (TGS6B) is 2.6.4,1 ', 6 '-three chloro-4 of sucralose, the cLogP of 1 ', 6 '-three deoxidations-6-O-acetic ester (TGS6A) is 0.18, the cLogP of dichlorogalactosucroand-6-acetic ester is that the cLogP of 0.06, one chlorine cane sugar-6-acetic ester is-0.85.
An embodiment according to the inventive method; R is alkyl, aryl or arylalkyl, and wherein the aryl moiety of aryl or arylalkyl randomly is selected from one or more substituting group replacement of halogen, haloalkyl, cyano group, nitro, alkoxyl group, alkyl sulfenyl, acyl group, acyloxy, sulfo-acyl group, acyl mercapto and aryloxy.In a particular; R ' is aryl (for example phenyl), and its one or more substituting group that randomly is selected from separately halogen, haloalkyl, cyano group, nitro, alkoxyl group, alkyl sulfenyl, acyl group, acyloxy, sulfo-acyl group, acyl mercapto and aryloxy replaces.In certain embodiments, R ' comprises hydrophobic polymer.For example, R ' can comprise hydrophobic or hydrophilic radical, but net result is the hydrophobic polymkeric substance of R ' in addition.
Can use in the present invention any suitable ester stable to chlorizating agent and that can be hydrolyzed.Described ester can be C
1-C
18Aliphatic ester, C
6-C
14Aryl C
1-C
18Aliphatic ester or C
6-C
14Aryl ester.Specially suitable carbonic ether comprises C
6-C
10Aryl carbonates, for example benzoic ether or naphthoate.Can prepare ester by acylating agent acidylate carbohydrate or the sugar with related acid, and in the situation that the carboxyl acidylate, acylating agent is acyl group acid anhydrides or acyl halide.Perhaps, can come the esterification carbohydrate by alkenyl esters.
In an embodiment of the inventive method, sugar ester is sucrose-6-ester, and chlorizate is the chloro sucrose-6-ester, 4 of sucralose, 1 ', 6 '-three chloro-4 in particular, 1 ', 6 '-three deoxidations-6-O-ester (TGS-6E).Sucrose-6-ester can prepare by the esterification of sucrose.According to above-mentioned each embodiment, the chlorizating agent that uses in described method is the acyl chlorides of acyl chlorides or activation.The example of acyl chlorides comprises thionyl chloride, sulfuryl chloride (sulfuryl chloride), phosgene, phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride and two (trichloromethyl) carbonic ether.
The example of acyl chlorides of activation comprises Wei Er David Smail reagent (Vilsmeier Reagent) (being also referred to as Arnold reagent (Arnold ' s reagent)), and it has structural formula [XYC=N
+R
2] Cl
-, wherein X is hydrogen, aryl or alkyl, wherein said aryl or alkyl are randomly replaced by halogen, alkoxyl group, thio alkoxy, acid amides or cyano group; Y is leavings group; R is hydrogen or the alkyl that randomly replaced by halogen, alkoxyl group, thio alkoxy, acid amides or cyano group.
According to an embodiment, in the formula of Wei Er David Smail reagent, Y is halogen, assorted alkyl or the group that can be replaced by the heteroatoms nucleophilic reagent, described heteroatoms nucleophilic reagent is tosylate/ester, p-bromobenzenesulfonate/ester, benzene sulfonate/ester, nitrobenzene-sulfonic acid salt/ester (nosylate), mesylate/ester, alkyl fluoride RF sulfonate/ester, trifluoro-methanyl sulfonate/ester, perfluoro butyl sulfosalt/ester (nonaflate) and trifluoroethyl sulfonate/ester (tresylate) for example, and is halogen in a particular instance.
According to an embodiment, in the formula of Wei Er David Smail reagent, X is hydrogen.According to another embodiment, in the formula of Wei Er David Smail reagent, R and X are alkyl.According to another embodiment, in the formula of Wei Er David Smail reagent, X is hydrogen, and Y is chlorine, and R is methyl.
Wei Er David Smail reagent can be for example reaction by acyl chlorides and acid amides produce, but and former state is used or react in advance the equivalent responses reagent of formation alternative with heteroatoms nucleophilic reagent YH.Such reagent is forming for before the chlorination reaction alternatively, but perhaps original position forms or buys from commercial source.In an example, Wei Er David Smail reagent can pass through N, the reaction of dinethylformamide and acyl chlorides produces, and for example, acyl chlorides is selected from thionyl chloride, sulfuryl chloride, phosgene, phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride and two (trichloromethyl) carbonic ether.
According to above-mentioned each embodiment, chlorination reaction can be carried out in solvent systems, for example, carries out in the solvent systems that comprises one or more of polar solvents, one or more of non-polar solvent or its mixture.In one embodiment, polar solvent is polar aprotic solvent.The example of polar aprotic solvent comprises DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetramethylene sulfone (sulfolane) and glycol ether and composition thereof.
In certain embodiments, solvent systems comprises polar aprotic solvent and the mixture that is selected from least a other aprotic solvent of hydrochloric ether and ether.The example of hydrochloric ether is chloroform, methylene dichloride, ethylene dichloride, cfc, Ethylene Dichloride, trieline, trichloropropane, trichloroethane, ethylene dichloride, tetrachloroethane and PFO and composition thereof.In one embodiment, ether is selected from tetrahydrofuran (THF), dioxane, methyl ethyl ether, Methylal(dimethoxymethane), glycol dimethyl ether, tetrahydropyrans, diglyme, isopropyl ether, ether and methyl tert-butyl ether and composition thereof.In a particular, solvent systems comprises DMF as polar aprotic solvent.
For example, carbohydrate-6-ester and chlorizating agent under suitable temp (for example ,-30 ℃ to 25 ℃) merge in solvent.During adding chlorizating agent, temperature does not usually allow to be increased to and surpasses approximately 60 ℃, in some embodiments, does not allow above 50 ℃.Usually, temperature is maintained at about 0 ℃ to approximately 30 ℃.Randomly, can remove any HCl that forms during the chlorization by any suitable method, described suitable method for example, by use vacuum, by supersound process, by the absorption of suitable adsorbent (such as carbon or zeolite) and/or by in reaction mixture, dividing gas (such as nitrogen, helium, air or argon gas) bubbling with inert water-free.
Chlorizating agent and carbohydrate or derivatives thereof to be chlorinated can react with suitable ratio, for example, with the ratio of 5 to 10 molar equivalents, the acyl chlorides of preferred 7 to 8 molar equivalents.
In above-mentioned each embodiment, described method also can comprise step (iv): the reaction mixture that cancellation at least a portion obtains in step (i), thus obtain the reaction mixture of cancellation.According to the present invention, can implement the cancellation step by any suitable method, described suitable method for example, with the reaction mixture (reaction mixture of preferred cooling, for example in the time of 5 ℃) be poured onto in the cold basic solution, for example, water slurry body, ammonium hydroxide aqueous solution or the pyridine/methanol solution of alkali metal hydroxide (such as sodium hydroxide or potassium hydroxide) water liquid, alkaline earth metal oxide or oxyhydroxide (such as calcium oxide or calcium hydroxide).
The reaction mixture of cancellation comprises chloro carbohydrate or derivatives thereof, for example the mixture of the carbohydrate or derivatives thereof of many chloros carbohydrate or derivatives thereof of expectation and one or more of chloro deficiencies.
According to an embodiment, the inventive method also can comprise step (v): the product mixtures that separates the carbohydrate or derivatives thereof that comprises many chloros carbohydrate or derivatives thereof and at least a chloro deficiency from the reaction mixture of cancellation.Can pass through the known any suitable method separated product mixture of those skilled in the art, described suitable method for example, by solvent or Solid-Phase Extraction, chromatography, crystallization, filtration or any other be fit to will expectation the mixture method of separating with the solvent of not expecting and/or impurity.
An embodiment according to described method, make the carbohydrate or derivatives thereof of described at least a chloro deficiency (for example be back to chlorinating step, be back to step (i)), thus the carbohydrate or derivatives thereof of further chlorination chloro deficiency.When the carbohydrate or derivatives thereof of chloro deficiency was back to chlorinating step, the carbohydrate or derivatives thereof of chloro deficiency can be used as the carbohydrate or derivatives thereof of specific chloro deficiency, as the mixture of the carbohydrate or derivatives thereof of chloro deficiency or as the mixture of the carbohydrate or derivatives thereof of chloro deficiency and other materials (such as many chloros carbohydrate or derivatives thereof) and return.
According to an embodiment of described method, the further chlorination of the carbohydrate or derivatives thereof of described at least a chloro deficiency occurs in the container that the container with generation step (i) separates.
According to an embodiment of described method, the further chlorination of the carbohydrate or derivatives thereof of described at least a chloro deficiency occurs in the same container with generation step (i).
In any embodiment, described method is continuous feeding method.
In above-mentioned each embodiment, obtain many chloros carbohydrate or derivatives thereof (for example sucralose-6-ester) in the step (i) and be at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% based on mole and/or based on the productive rate of quality.
In above-mentioned each embodiment, obtain many chloros carbohydrate or derivatives thereof (for example sucralose-6-ester) in the step (iii) and be at least 50%, at least 60%, at least 70%, at least 80% or at least 90% based on mole and/or based on the productive rate of quality.
According to an embodiment of described method, by solvent extraction separated product mixture from the reaction mixture of cancellation.The solvent that is used for extraction preferably with the immiscible solvent of water, for example, ethyl acetate, halohydrocarbon or any other form the solvent of two-phase hydrophobic (organic) layer and hydrophilic (water) layer, and it can be with expectation product mixtures and the separation of other impurity and extracting and separating physically.This does not get rid of incomplete separation, is dissolved in the water layer some of them product retaining part, needs subsequently extraction.This does not get rid of incomplete separation yet, and the some of them organic solvent partly is dissolved in the water layer (for example, DMF, DMA, ethyl acetate etc.) or organic solvent partly is dissolved in (for example, water, alcohol etc.) in the water layer.Optionally extract is decoloured to remove the foreign pigment of not expecting.Can decolour by any appropriate method (for example, by using activated carbon treatment).
According to one embodiment of the invention, described method also can comprise step (vi): the product mixtures that will separate in step (v) is divided into the second fraction that (a) comprises the first fraction of many chloros carbohydrate or derivatives thereof and (b) comprise the carbohydrate or derivatives thereof of at least a chloro deficiency.Can separate by any suitable method, described suitable method for example utilizes many chloros carbohydrate or derivatives thereof with respect to the solvent extraction of the different solubilities character of the carbohydrate or derivatives thereof of chloro deficiency.
The first fraction can only contain many chloros carbohydrate or derivatives thereof or comprise many chloros carbohydrate or derivatives thereof and the mixture of the carbohydrate or derivatives thereof of at least a chloro deficiency; But, when it was the mixture of carbohydrate or derivatives thereof of many chloros carbohydrate or derivatives thereof and at least a chlorination deficiency, the first step was divided and is comprised the many chloro carbohydrate or derivatives thereof excessive with respect to the carbohydrate or derivatives thereof of chloro deficiency.
The carbohydrate that comprises at least a chloro deficiency or derivatives thereof is divided in the second stage.The second fraction can only comprise the carbohydrate or derivatives thereof of one or more of chloro deficiencies, perhaps can comprise the carbohydrate or derivatives thereof of one or more of chloro deficiencies and the mixture of many chloros carbohydrate or derivatives thereof; But, when it was the mixture of the carbohydrate or derivatives thereof of chloro deficiency and many chloros carbohydrate or derivatives thereof, the carbohydrate or derivatives thereof that comprises the chloro deficiency excessive with respect to many chloros carbohydrate or derivatives thereof was divided in the second stage.
According to one embodiment of the invention, the carbohydrate or derivatives thereof of many chloros carbohydrate or derivatives thereof, chloro deficiency or their mixture randomly merge with other carbohydrate or derivatives thereof and are back to another chlorinating step (for example, the step of described method (i)) with the carbohydrate or derivatives thereof of further chlorination chloro deficiency and the described other carbohydrate or derivatives thereof of chlorination randomly.
In a specific embodiments, the invention provides be used to making the chlorination of carbohydrate or derivatives thereof obtain the method for many chloros carbohydrate or derivatives thereof, the chlorine atom that the desired location of described many chloros carbohydrate or derivatives thereof in its molecular structure has desired number, described method comprises:
(i) the carbohydrate or derivatives thereof is dissolved in the aprotic solvent system, obtains comprising the solution of described carbohydrate or derivatives thereof;
(ii) will merge from the solution that comprises described carbohydrate or derivatives thereof and the chlorizating agent of step (i), obtain chlorinated mixture;
(iii) heat described chlorinated mixture, obtain the mixture of chloro carbohydrate or derivatives thereof, it comprises many chloros carbohydrate or derivatives thereof and at least a carbohydrate or derivatives thereof with chloro deficiency of the chlorine atom that is less than desired number of expectation;
(iv) make the carbohydrate or derivatives thereof of at least a chloro deficiency be back to chlorinating step, thus the carbohydrate or derivatives thereof of the further described at least a chloro deficiency of chlorination; Randomly
(v) repeating step (ii) to (iv) " n " is inferior, wherein n 〉=1.
Aforesaid method also can comprise step (vi): described many chloros carbohydrate or derivatives thereof is separated with the carbohydrate or derivatives thereof of described at least a chloro deficiency.
According to an embodiment of aforesaid method, make the carbohydrate or derivatives thereof of described at least a chloro deficiency be back to step (i) with further chlorination.
According to an embodiment of aforesaid method, the further chlorination of the carbohydrate or derivatives thereof of described at least a chloro deficiency occurs in the container that the container with generation step (i) separates.
According to an embodiment of aforesaid method, the further chlorination of the carbohydrate or derivatives thereof of described at least a chloro deficiency occurs in the same container with generation step (i).
In any embodiment, aforesaid method is continuous feeding method.
According to above-mentioned each embodiment, the carbohydrate or derivatives thereof of chloro deficiency has one or two chlorine atom in its molecular structure.According to above-mentioned each embodiment, the desired number of the chlorine atom that exists in many chloros carbohydrate or derivatives thereof is 3.
In above-mentioned each embodiment, the chlorination reaction of carrying out after the carbohydrate or derivatives thereof of chloro deficiency reclaims and returns can repeat arbitrary number of times, and in a particular, is repeated to reach steady state.In one embodiment, can be take step (iii) or " n " value as 2 to 8,3 to 7,4 to 6 or 5 (v) reclaim and return.
In any embodiment, except the carbohydrate or derivatives thereof that makes the chloro deficiency reclaims and is back to the initial chlorinating step, non-chloro carbohydrate or derivatives thereof (for example, new sucrose-6-ester) in addition can merge with the carbohydrate or derivatives thereof of the chloro deficiency of returning.
In above-mentioned each embodiment, in step (i), obtain sucralose-6-ester and be at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% based on mole and/or based on the productive rate of quality.
In above-mentioned each embodiment, in step (v), obtain sucralose-6-ester and be at least 50%, at least 60%, at least 70%, at least 80% or at least 90% based on mole and/or based on the productive rate of quality.
The present invention also provides the method for preparing Sucralose, and it comprises makes the many chloros sucralose-6-ester degreasing that obtains according to above-mentioned each embodiment to obtain Sucralose.For example, can carry out degreasing by the basic hydrolysis of ester; Referring to for example US ' 463, the 9 hurdles, the capable and embodiment 16 of 4-40, its disclosure is merged in by reference.
Following examples further for example understand the present invention, but certainly it can not be interpreted as limit by any way its scope.
Embodiment
The present embodiment has confirmed to prepare according to one embodiment of the invention the method for Sucralose.0.05 mole of Sucrose-6-benzoate (S6B) (22.6 gram) is joined in the anhydrous DMF of 850mL (DMF), and fore-distillation is to steady temperature (41 ℃, the 75mL distillment) under the perfect vacuum.DMF solution is cooled to 5 ℃ (ice baths) and adds 0.4 mole of Wei Er David Smail (8 equivalents, 52 grams).The light yellow suspension of gained stirred and be warming up to envrionment temperature through 30 minutes, then be heated to 60 ℃ and kept 3 hours, this moment, suspension became the light orange uniform solution.TLC the analysis showed that and no longer has S6B.Behind the cooling solution, the 600mL DMF-HCl (approximately 0.4M) that distillation forms during chlorination reaction under the perfect vacuum.Then the gained reaction mixture is heated to 87 ℃ and kept 8 hours.Reaction mixture is cooled to 5 ℃ and be poured onto in the cold ammonium hydroxide water liquid of 500mL.(2 * 500mL) to extract 4,1 ', 6 '-three chloro-4 of sucralose, the sucralose product of 1 ', 6 '-three deoxidations-6-O-benzoic ether and any part chloro or chloro deficiency with ethyl acetate extraction with the gained mixture.By stirring with gac (10g) to the extract decolouring, extract is concentrated by diatomite filtration and under vacuum.The gained resistates is dissolved in the ethyl acetate (100mL) and (2 * 50mL) to remove remaining DMF with the salt water washing.Products therefrom drying under vacuum was obtained 19 gram amorphous foam shape solids further to remove DMF in 30 minutes.Then with the spumescence dissolution of solid in the mixture of methyl-tert butyl ester (150mL) and water (5mL).Be precipitated as pale solid at strong stirring TGS6B after 30 minutes (13.9g, 62% productive rate by mass, purity＞95%), and collect by filtering.Filtrate (mother liquor) is concentrated into 8 grams.
Said process is carried out repetition in the ratio of 8 gram mother liquors, and difference is: (175mLDMF original volume, 15mL fore-distillation, 7 equivalent Wei Er David Smail 20g), reaction only kept 30 minutes at 60 ℃, and second distillation distills out 125mL DMF.This repeats to provide the TGS6B of another batch (4.1g, 18% productive rate by weight, purity＞95%) for 80% merging productive rate by weight.Also reclaimed other 3 gram mother liquors, it comprises approximately 1: 1 mixture of dichloro-and/or three chloro sucrose esters and the initial high R of same amount
fMaterial.Each chlorination reaction was carried out under 87 ℃ 8-10 hour.
The productive rate that obtains is as follows: repeat for the first time: 56% mole, and 62% quality; Repeat for the second time: 16.5% mole, 18% quality (based on initial reaction); The merging productive rate of twice repetition is: 72.5% mole, and 80% quality.If comprise mother liquor, then merging productive rate is 84% mole, 93% quality.
All reference that comprise publication, patent application and patent that this paper quotes are incorporated this paper by reference into, and its degree is as separately and the degree incorporated into by reference of each reference that particularly points out and in this article with its whole proposition.
In describing context of the present invention (especially in the context in following claim) should be interpreted as comprising when the usage quantity word is modified odd number and plural number both, unless this paper points out in addition or is clearly contradicted by context.Unless otherwise noted, otherwise term " comprises (comprising) ", " having (having) ", " comprising (including) " and " containing (containing) " should be interpreted as open-ended term (namely, the meaning is " including, but are not limited to ").Unless otherwise noted, otherwise this paper only is intended to as each independent convenient method of value of pointing out to drop on separately in the scope the description of the scope of value, and each independent value incorporates in the explanation, just quotes separately in this article as it.All methods described herein can be carried out with any suitable order, unless this paper points out in addition or is clearly contradicted by context.Unless stated otherwise, otherwise the use of any and whole example provided herein or exemplary language (for example, " for example ") only is intended to illustrate better the present invention, rather than is intended to limit the scope of the invention.Do not have in the specification sheets language should be interpreted as indicating the key element of any failed call right be of the present invention put into practice necessary.
This paper describes the preferred embodiments of the invention, it comprises that known being used for of the inventor implement optimal mode of the present invention.After reading above stated specification, the variant of those preferred embodiments can become obvious to those skilled in the art.The inventor expects that the technician suitably uses such variant, the to be put into practice invention of inventor's expection except this paper specifically describes.Therefore, allow such as applicable law, the present invention includes whole modifications and the equivalent of the theme that this claim of investing quotes.In addition, its might variant in any combination of above-mentioned key element all covered among the present invention, unless this paper points out in addition or it is clearly contradicted by context.
Claims (65)
1. be used for making the chlorination of carbohydrate or derivatives thereof to produce the method for many chloros carbohydrate or derivatives thereof, described many chloros carbohydrate or derivatives thereof has the chlorine atom of desired number at the desired location of its molecular structure, and described method comprises:
(i) make described carbohydrate or derivatives thereof and chlorination reaction, obtain comprising the reaction mixture of the carbohydrate or derivatives thereof of described many chloros carbohydrate or derivatives thereof and at least a chloro deficiency;
(ii) make the carbohydrate or derivatives thereof of described at least a chloro deficiency be back to chlorinating step and the further carbohydrate or derivatives thereof of the described at least a chloro deficiency of chlorination, obtain many chloros carbohydrate or derivatives thereof of expecting; With
(iii) randomly repeating step (i) and (ii) " n " inferior, n 〉=1 wherein.
2. method according to claim 1, it also comprises:
(iv) cancellation at least a portion obtains the reaction mixture of cancellation from the described reaction mixture of step (i); With
(v) from the reaction mixture of described cancellation, separate the product mixtures of the carbohydrate or derivatives thereof comprise many chloros carbohydrate or derivatives thereof and at least a chloro deficiency.
3. method according to claim 1 wherein makes the carbohydrate or derivatives thereof of described at least a chloro deficiency be back to step (i) with further chlorination.
4. method according to claim 1, the further chlorination of the carbohydrate or derivatives thereof of wherein said at least a chloro deficiency occur in the container that the container with generation step (i) separates.
5. method according to claim 1, the further chlorination of the carbohydrate or derivatives thereof of wherein said at least a chloro deficiency occur in the same container with generation step (i).
6. each described method in 5 according to claim 1, it is continuous feeding method.
7. method according to claim 2 wherein in step (v), is separated described product mixtures by solvent extraction from the reaction mixture of described cancellation.
8. according to claim 2 or 7 described methods, it also comprises: the described product mixtures that (vi) will separate in step (v) is divided into the second fraction that (a) comprises the first fraction of described many chloros carbohydrate or derivatives thereof and (b) comprise the carbohydrate or derivatives thereof of at least a chloro deficiency.
9. each described method in 8 according to claim 1, the carbohydrate or derivatives thereof of wherein said many chloros carbohydrate or derivatives thereof, chloro deficiency or their mixture randomly merge with other carbohydrate or derivatives thereof and are back to chlorinating step or step (i).
10. each described method in 9 according to claim 1, wherein said carbohydrate or derivatives thereof is sugared or derivatives thereof.
11. method according to claim 10, wherein said sugar derivatives is sugar ester.
12. method according to claim 11, wherein said sugar ester is sucrose-6-ester.
13. each described method in 12 according to claim 1, wherein said many chloros carbohydrate derivates is 4,1 ', 6 '-three chloro-4 of sucralose, 1 ', 6 '-three deoxidations-6-O-ester (TGS-6E).
14. each described method in 13 according to claim 11, the ester of wherein said many chloros carbohydrate ester or described chloro deficiency has formula:
M-OC(＝O)R’，
Wherein R ' comprises hydrophobic grouping or hydrophobic polymer, and M is that the ester that replenishes described many chloros carbohydrate ester or chloro deficiency makes it complete part.
15. method according to claim 14, wherein R ' comprises hydrophobic grouping or hydrophobic polymer, thereby the octanol-water partition coefficient cLogP of the ester of described many chloros carbohydrate ester or described chloro deficiency is-0.5 or larger.
16. method according to claim 14, the octanol-water partition coefficient cLogP of the ester of wherein said many chloros carbohydrate ester or described chloro deficiency is 0 or greater than 0.
17. method according to claim 14; wherein R is alkyl, aryl or arylalkyl, and wherein the aryl moiety of aryl or arylalkyl randomly is selected from one or more substituting group replacement of halogen, haloalkyl, cyano group, nitro, alkoxyl group, alkyl sulfenyl, acyl group, acyloxy, sulfo-acyl group, acyl mercapto and aryloxy.
18. method according to claim 14, wherein R ' is aryl.
19. method according to claim 18, wherein R ' is phenyl.
20. method according to claim 14, wherein R ' comprises hydrophobic polymer.
21. each described method in 20 according to claim 1, wherein said chlorizating agent is the acyl chlorides of acyl chlorides or activation.
22. method according to claim 21, wherein said acyl chlorides are selected from thionyl chloride, sulfuryl chloride, phosgene, phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride and two (trichloromethyl) carbonic ether.
23. method according to claim 21, the acyl chlorides of wherein said activation are Wei Er David Smail reagent (or Arnold reagent), it has structural formula [XYC=N
+R
2] Cl
-, wherein X is hydrogen, aryl or alkyl, wherein said aryl or alkyl are randomly replaced by halogen, alkoxyl group, thio alkoxy, acid amides or cyano group; Y is leavings group; R is hydrogen or the alkyl that randomly replaced by halogen, alkoxyl group, thio alkoxy, acid amides or cyano group.
24. method according to claim 23, wherein Y is halogen, assorted alkyl or the group that can be replaced by the heteroatoms nucleophilic reagent.
25. method according to claim 24, wherein Y is halogen.
26. method according to claim 23, wherein X is hydrogen.
27. method according to claim 23, wherein R and Y are alkyl.
28. each described method in 26 according to claim 23, wherein X is hydrogen, and Y is chlorine, and R is methyl.
29. method according to claim 28, wherein said Wei Er David Smail reagent produces by the reaction of DMF and acyl chlorides.
30. method according to claim 29, wherein said acyl chlorides are selected from thionyl chloride, sulfuryl chloride, phosgene, phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride and two (trichloromethyl) carbonic ether.
31. each described method in 30 according to claim 1, wherein said chlorination reaction is carried out in solvent systems.
32. method according to claim 31, wherein said solvent systems comprise one or more of polar solvents, one or more of non-polar solvent or their mixture.
33. method according to claim 32, wherein said polar solvent is polar aprotic solvent.
34. method according to claim 33, wherein said polar aprotic solvent is selected from DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, methyl-sulphoxide, tetramethylene sulfone and glycol ether.
35. method according to claim 31, wherein said solvent systems comprise polar aprotic solvent and are selected from the mixture of at least a other aprotic solvent of hydrochloric ether and ether.
36. method according to claim 35, wherein said hydrochloric ether is selected from chloroform, methylene dichloride, ethylene dichloride, cfc, Ethylene Dichloride, trieline, trichloropropane, trichloroethane, ethylene dichloride, tetrachloroethane and PFO.
37. method according to claim 35, wherein said ether is selected from tetrahydrofuran (THF), dioxane, methyl ethyl ether, Methylal(dimethoxymethane), glycol dimethyl ether, tetrahydropyrans, diglyme, isopropyl ether, ether and methyl tert-butyl ether.
38. each described method in 37 according to claim 32, wherein said solvent systems comprises that DMF is as polar aprotic solvent.
39. be used for making the chlorination of carbohydrate or derivatives thereof to obtain the method for many chloros carbohydrate or derivatives thereof, described many chloros carbohydrate or derivatives thereof has the chlorine atom of desired number at the desired location of its molecular structure, described method comprises:
(i) described carbohydrate or derivatives thereof is dissolved in the aprotic solvent system, obtains comprising the solution of described carbohydrate or derivatives thereof;
(ii) will merge from the described solution that comprises described carbohydrate or derivatives thereof and the chlorizating agent of step (i), obtain chlorinated mixture;
(iii) heat described chlorinated mixture, obtain the mixture of chloro carbohydrate or derivatives thereof, it comprises many chloros carbohydrate or derivatives thereof and at least a carbohydrate or derivatives thereof with chloro deficiency of the chlorine atom that is less than desired number of described expectation;
(iv) make the carbohydrate or derivatives thereof of at least a chloro deficiency be back to chlorinating step, thus the carbohydrate or derivatives thereof of the further described at least a chloro deficiency of chlorination; Randomly
(v) repeating step (ii) to (iv) " n " is inferior, wherein n 〉=1.
40. described method according to claim 39, it comprises that also (vi) separates the carbohydrate or derivatives thereof of described many chloros carbohydrate or derivatives thereof with described at least a chloro deficiency.
41. described method wherein makes the carbohydrate or derivatives thereof of described at least a chloro deficiency be back to step (i) with further chlorination according to claim 39.
42. described method according to claim 39, the further chlorination of the carbohydrate or derivatives thereof of wherein said at least a chloro deficiency occur in the container that the container with generation step (i) separates.
43. described method according to claim 39, the further chlorination of the carbohydrate or derivatives thereof of wherein said at least a chloro deficiency occur in the same container with generation step (i).
44. each described method in 43 according to claim 39, it is continuous feeding method.
45. each described method in 44 according to claim 1, wherein said many chloros carbohydrate or derivatives thereof is many chloros sucrose-6-ester.
46. described method according to claim 45, wherein said many chloros carbohydrate is sucralose-6-ester.
47. described method according to claim 46, the productive rate that wherein obtains described sucralose-6-ester in step (i) is at least 30%.
48. described method according to claim 47, the productive rate that wherein obtains described sucralose-6-ester in step (i) is at least 40%.
49. described method according to claim 48, the productive rate that wherein obtains described sucralose-6-ester in step (i) is at least 50%.
50. described method according to claim 39, the productive rate that wherein obtains described sucralose-6-ester in step (v) is at least 50%.
51. described method according to claim 50, the productive rate that wherein obtains sucralose-6-ester in step (v) is at least 60%.
52. 1 described method according to claim 5, the productive rate that wherein obtains described sucralose-6-ester in step (v) is at least 70%.
53. 2 described methods according to claim 5, the productive rate that wherein obtains sucralose-6-ester in step (v) is at least 80%.
54. 3 described methods according to claim 5, the productive rate that wherein obtains sucralose-6-ester in step (v) is at least 90%.
55. method according to claim 1, the productive rate that wherein obtains described many chloros carbohydrate or derivatives thereof in step (i) is at least 30%.
56. 5 described methods according to claim 5, the productive rate that wherein obtains described many chloros carbohydrate or derivatives thereof in step (i) is at least 40%.
57. 6 described methods according to claim 5, the productive rate that wherein obtains described many chloros carbohydrate or derivatives thereof in step (i) is at least 50%.
58. method according to claim 1, the productive rate that wherein obtains described many chloros carbohydrate or derivatives thereof in step (iii) is at least 50%.
59. 8 described methods according to claim 5, the productive rate that wherein obtains many chloros carbohydrate or derivatives thereof in step (iii) is at least 60%.
60. 9 described methods according to claim 5, the productive rate that wherein obtains described many chloros carbohydrate or derivatives thereof in step (iii) is at least 70%.
61. 0 described method according to claim 6, the productive rate that wherein obtains many chloros carbohydrate or derivatives thereof in step (iii) is at least 80%.
62. 1 described method according to claim 6, the productive rate that wherein obtains many chloros carbohydrate or derivatives thereof in step (iii) is at least 90%.
63. prepare the method for Sucralose, it comprises makes according to claim 1 in 62 each described many chloros sucrose 6-ester degreasing that obtains to obtain Sucralose.
64. each described method in 62 according to claim 1, the carbohydrate or derivatives thereof of wherein said chloro deficiency has one or two chlorine atom in its molecular structure.
65. according to claim 1 or 39 described methods, the desired number of the chlorine atom that exists in wherein said many chloros carbohydrate or derivatives thereof is 3.
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| CN103328495B CN103328495B (en) | 2016-10-05 |
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| CN105131050B (en) * | 2015-07-22 | 2018-07-31 | 青岛科技大学 | A kind of preparation method of chlorinating agent and its method for preparing Sucralose |
| CN106589013A (en) * | 2016-11-11 | 2017-04-26 | 浙江新和成股份有限公司 | Method of preparing sucralose-6-acetate in liquid-liquid two-phase system |
| CN106589013B (en) * | 2016-11-11 | 2019-06-04 | 浙江新和成股份有限公司 | A method of sucralose-6-acetic ester is prepared in liquid-liquid diphase system |
Also Published As
| Publication number | Publication date |
|---|---|
| DK2646452T3 (en) | 2016-06-20 |
| CA2823961A1 (en) | 2013-04-18 |
| EP2646452A1 (en) | 2013-10-09 |
| ES2574261T3 (en) | 2016-06-16 |
| EP2646452B1 (en) | 2016-03-09 |
| MX2013007764A (en) | 2014-02-11 |
| HUE027876T2 (en) | 2016-10-28 |
| WO2013056128A1 (en) | 2013-04-18 |
| US20130197215A1 (en) | 2013-08-01 |
| CA2823961C (en) | 2020-10-06 |
| AU2012323934A1 (en) | 2013-07-11 |
| MX342969B (en) | 2016-10-20 |
| PT2646452E (en) | 2016-06-17 |
| CY1117609T1 (en) | 2017-04-26 |
| US8691797B2 (en) | 2014-04-08 |
| US20140187768A1 (en) | 2014-07-03 |
| SG2013049648A (en) | 2014-12-30 |
| CN103328495B (en) | 2016-10-05 |
| AU2012323934B2 (en) | 2017-06-29 |
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